Progress in the early detection and treatment of cancer requires accurate model systems to further evaluate new, promising discoveries. Small animal, and in particular mouse, model systems are attractive to researchers for numerous reasons, including their ease of use and well-described platforms. Immunotherapy has revolutionized clinical oncology, but lacks pre-clinical models of the human immune system and human cancer to investigate new modalities and limitations/toxicities of treatment regimens. The ability to grow human tumors in immune-deficient mice (so-called patient-derived xenografts, or PDXs) allows researchers to work directly with human cancer tissue in a controlled setting. However, PDX models are limited by their lack of an intact immune system. The broad objective of this proposal is to validate an in vivo model to evaluate human tumors in the context of a complete and intact human immune system in a completely personalized and autologous fashion to study cancer immunotherapy. Herein, we propose to: (1) validate the ability of our humanized system to serve as a model for cancer immunotherapy treatment response and toxicity in patients with melanoma, including immunotherapy checkpoint blockade and vaccine strategies, and to (2) extend our current work in melanoma by validating the ability to establish humanized mice and evaluate tumor growth and leukocyte development in autologous human pancreatic and colorectal tumors established in humanized mice. In each of these areas, we will leverage our multi-institutional team's individual expertise along with our institutional infrastructure to maximize the success of the experimental aims. The results from this project will made widely available to the general research community for future, hypothesis-driven research. Taken together, the studies described in this research proposal will meet multiple goals and address several unmet needs identified in this grant opportunity, thus significantly enhancing the applicability of a fully autologous and immunocompetent precision model system for use in translational oncology research.